Intrauterine growth retardation (IUGR) has been linked to later development of type 2 diabetes in adulthood. Emerging data suggest that epigenetics may be an underlying mechanism. Decreased Pdx1 expression, a key regulator of ss-cell growth and function, plays a pivotal role in the development of diabetes in humans as well as in IUGR animals. One of the earliest molecular events involved in silencing the Pdx1 promoter in fetal pancreas of IUGR animals is the loss of USF1 binding. This is coincident with histone deacetylation, which suggests that in the absence of USF1, chromatin reverts to a heterochromatin conformation leading to transcriptional silencing. We suggest that USF1 binding establishes an active chromatin domain by recruiting histone modifying enzymes which maintain high levels of histone acetylation and methylation at Pdx1 as well as at other genes regulated by USF1 in the ss-cell. In previous studies we identified extensive genomic DNA hypermethylation and hypomethylation in IUGR islets. These alterations in DNA methylation were in highly conserved intergenic sequences and were associated with significant changes in expression of adjacent genes, suggesting that these may represent cis-regulatory sites (distal enhancers). Taken together, these studies and our data suggest DNA methylation and histone modifications interact at intergenic loci to regulate gene expression.
Specific Aim 1 : To test the hypotheses that USF1 recruits histone-modifying enzymes that maintain H3 acetylation and H3K4 methylation, and that loss of USF1 binding initiates chromatin remodeling in ss-cells.
Specific Aim 2 : To test the hypothesis that changes in DNA methylation in combination with histone modifications at intergenic loci (distal enhancers) alter gene expression in IUGR islets.
Specific Aim 3 : To test the hypothesis that the mechanism by which gene expression is increased in IUGR islets occurs through the induction of histone modifications, which in turn drive the loss of DNA methylation.

Public Health Relevance

The studies outlined in this proposal will be the first to directly link epigenetic modifications to a disease state. Determining the mechanisms underlying aberrant DNA methylation and histone modifications will further our understanding of this complex process and will enable us to develop new therapeutic agents to treat diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK055704-10
Application #
8323871
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Appel, Michael C
Project Start
2000-06-01
Project End
2015-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
10
Fiscal Year
2012
Total Cost
$313,200
Indirect Cost
$117,450
Name
University of Pennsylvania
Department
Pediatrics
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Jaeckle Santos, Lane J; Li, Changhong; Doulias, Paschalis-Thomas et al. (2014) Neutralizing Th2 inflammation in neonatal islets prevents β-cell failure in adult IUGR rats. Diabetes 63:1672-84
Simmons, R A (2013) Programming of DNA methylation in type 2 diabetes. Diabetologia 56:947-8
Simmons, Rebecca A (2013) Preeclampsia and prematurity as precursors to adolescent obesity. J Pediatr 162:889-90
Gatford, Kathryn L; Simmons, Rebecca A (2013) Prenatal programming of insulin secretion in intrauterine growth restriction. Clin Obstet Gynecol 56:520-8
Reid, Mary V; Murray, Kaitlin A; Marsh, Eric D et al. (2012) Delayed myelination in an intrauterine growth retardation model is mediated by oxidative stress upregulating bone morphogenetic protein 4. J Neuropathol Exp Neurol 71:640-53
Pinney, Sara E; Simmons, Rebecca A (2012) Metabolic programming, epigenetics, and gestational diabetes mellitus. Curr Diab Rep 12:67-74
Simmons, Rebecca A (2012) Developmental origins of diabetes: The role of oxidative stress. Best Pract Res Clin Endocrinol Metab 26:701-8
Calabria, Andrew C; Gallagher, Paul R; Simmons, Rebecca et al. (2011) Postoperative surveillance and detection of postprandial hypoglycemia after fundoplasty in children. J Pediatr 159:597-601.e1
Pinney, S E; Jaeckle Santos, L J; Han, Y et al. (2011) Exendin-4 increases histone acetylase activity and reverses epigenetic modifications that silence Pdx1 in the intrauterine growth retarded rat. Diabetologia 54:2606-14

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